CN105056298B - A kind of porous calcium phosphate microsphere material with surface macropore, preparation method and application - Google Patents
A kind of porous calcium phosphate microsphere material with surface macropore, preparation method and application Download PDFInfo
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- CN105056298B CN105056298B CN201510528397.6A CN201510528397A CN105056298B CN 105056298 B CN105056298 B CN 105056298B CN 201510528397 A CN201510528397 A CN 201510528397A CN 105056298 B CN105056298 B CN 105056298B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/02—Inorganic materials
- A61L27/12—Phosphorus-containing materials, e.g. apatite
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/56—Porous materials, e.g. foams or sponges
Abstract
The invention discloses a kind of preparation method of the porous calcium phosphate microsphere material with surface macropore, comprise the following steps：Polysaccharide gum is dissolved in deionized water, polysaccharide gum solution is made；(2) thickener is dissolved in deionized water, thickener soln is made；(3) polysaccharide gum solution and thickener soln are mixed, obtains polysaccharide gum/thickener soln；(4) calcium phosphate bone cement powder and polysaccharide gum/thickener soln are mixed, obtains calcium phosphate bone cement slurry；(5) by after calcium phosphate bone cement slurry high-speed stirred through be ultrasonically treated；Slurry is added drop-wise in liquid nitrogen；The microballoon of freezing is conserved, is dried in vacuo, obtains the porous calcium phosphate microsphere with surface macropore.The invention also discloses with the porous calcium phosphate microsphere material of surface macropore and its application.The porous calcium phosphate microsphere material with surface macropore of the present invention, have surface macropore, porosity height, pore communication good, there is good anti-disintegrating property.
Description
Technical field
The present invention relates to belonging to bone defect healing medical field, more particularly to a kind of porous calcium phosphate with surface macropore
Micro-sphere material, preparation method and application.
Background technology
The artificial bone for clinically substituting Cranial defect position is mainly calcium phosphate material, including hydroxyapatite pottery
Porcelain, bata-tricalcium phosphate ceramics, biphasic calcium phosphate, calcium phosphate bone cement, bioactivity glass and various calcium orthophosphate base composite woods
Material.In general, application form of the calcium phosphate material in Bone Defect Repari field mainly has fine and close and porous two by the division of its structure
Type.Dense form bone renovating material, its porosity is too low, is unfavorable for tissue and cell is grown into and angiogenesis, influence material
The biology performance of material.And the hole that connection in material be present can be the phase between blood conveying, nutriment and metabolite
Growing into etc. for interchangeable, blood vessel and tissue provides passage.There is scholar to think, macropore of the size more than 100 μm is advantageous to tissue
Grow into, so exploitation with higher porosity calcium phosphate bone repair materials it is most important.
Studies have reported that the preparation method of porous calcium phosphate calcium material mainly has：Pavticulate percolation, freeze-drying,
Gas foaming method, rapid prototyping (also referred to as 3D printing), addition pore creating material method etc..However, by changing pore creating material or solvable grain
Although the methods of size such as mannitol, degradable macromolecule microballoon, sodium chloride of son, can regulate and control the hole inside calcium phosphate material
Footpath size, but it is connective poor between the hole formed, and based on closed pore, most holes do not connect with outside.Phase
Interconnected three-dimensional pore space can be formed than tightly packed between porous block material, microballoon, is advantageous to blood vessel and bone
Tissue is grown into；Secondly, microballoon has good mobility, may be implemented in any filling of irregular bone defect.Phosphoric acid
Calcium bone cement has self-curing, and curing reaction can occur in body temperature or at room temperature, with needing the calcium phosphate through high temperature sintering to make pottery
Porcelain is compared, more conducively the load of bioactive substance and medicine.But it is used as bone prosthetic material, calcium phosphate bone cement microballoon
Though itself is rich in micropore but lacks the poor connectivity between macropore, hole, it is unfavorable for blood vessel and bone tissue and is grown to material internal；
In addition, its degradation speed is slow, the speed of growth of new bone can not be matched.Porosity, pore-size and its distribution, hole in material
Application of the connectivity pair in bone renovating material clinically between gap has a material impact, macropore be advantageous to new bone growth and
The generation of blood vessel, micropore are advantageous to the adhesion of albumen and the transmission of nutriment.Therefore, there is the calcium phosphate of connected porous structure
Microballoon has good practical value as bone renovating material.
The content of the invention
In order to overcome the disadvantages mentioned above of prior art and deficiency, it is an object of the invention to provide one kind to have surface macropore
Porous calcium phosphate microsphere material preparation method, need not move through high temperature sintering processing, can obtain with surface macropore, porosity
Calcium phosphate microsphere high, pore communication is good.
The purpose of the present invention is achieved through the following technical solutions：
A kind of preparation method of the porous calcium phosphate microsphere material with surface macropore, comprises the following steps：
(1) polysaccharide gum is dissolved in 25~80 DEG C of deionized waters, the polysaccharide gum solution that concentration is 2%~20%w/v is made；
(2) thickener is dissolved in 25~80 DEG C of deionized waters, it is molten that the thickener that concentration is 0.1%~5%w/v is made
Liquid；
(3) mixing of thickener soln that the polysaccharide gum solution and step (2) obtained step (1) obtains, obtain polysaccharide gum/
Thickener mixed solution, the liquid phase as calcium phosphate bone cement；
(4) polysaccharide gum for obtaining step (3)/thickener mixed solution and calcium phosphate bone cement powder by liquid-solid ratio 2~
5mL/g is sufficiently mixed, stirred by 400~1200r/min of speed, and mixing time is 20~40min, and the phosphorus rich in bubble is made
Sour calcium bone cement slurry；
(5) the calcium phosphate bone cement slurry rich in bubble obtained in step (4) is placed in ultrasonic oscillator, ultrasound
Frequency is 16~40kHz, and ultrasonic time is 5~30min；
(6) the calcium phosphate bone cement slurry in step (5) is added drop-wise to the syringe that syringe needle internal diameter is 0.5~1.5mm
In liquid nitrogen, obtain freezing bone cement microballoon；Will freezing bone cement microballoon be placed in 25~60 DEG C, relative humidity be 90%~100%
Environment in conserve aquation 1~7 day, vacuum drying, obtain the porous calcium phosphate microsphere with surface macropore；The hole of the macropore
Footpath is 20~85 μm.
Polysaccharide gum described in step (1) is converted starch, gelatin, xanthans, soluble chitosan, hydroxyethyl cellulose,
At least one of dextrin, Arabic gum, carragheen, guar gum.
Thickener described in step (2) is modified starch, oxidized starch, sodium carboxymethylcellulose, HPMC,
At least one of sodium alginate, polyvinyl alcohol, pectin, hydroxypropyl methyl cellulose.
Calcium phosphate bone cement described in step (4) is " tetracalcium phosphate-calcium monohydrogen phosphate " system bone cement, " calcium dihydrogen phosphate-
Type alpha tricalcium phosphate-calcium carbonate " system bone cement, " tetracalcium phosphate-type alpha tricalcium phosphate " system bone cement, " tetracalcium phosphate-β-phosphoric acid
DFP-calcium dihydrogen phosphate " system bone cement, " amorphous calcium phosphate-calcium monohydrogen phosphate " system bone cement, " partially crystallized calcium phosphate-
Any one in calcium monohydrogen phosphate " system bone cement or " calcium monohydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system bone cement.
The preparation method of the described porous calcium phosphate microsphere material with surface macropore is prepared big with surface
The porous calcium phosphate microsphere material in hole, it is interconnected between the porous calcium phosphate microsphere hole, inside bore dimension is 100~
160μm。
The porous calcium phosphate microsphere material with surface macropore is as medical Cranial defect packing material or as medicine
Carrier material.
During the application as medical Cranial defect packing material, it is specially：It is appropriate according to the size at Cranial defect position, selection
The porous calcium phosphate microsphere with surface macropore of particle diameter is filled into Cranial defect position, and stitching processing is carried out to wound.
The porous calcium phosphate microsphere with surface macropore is drug bearing microsphere.
The drug bearing microsphere, specific preparation method are：The microballoon made is soaked in drug solution, passes through liquid phase adsorption
Form be loaded into medicine.
The drug bearing microsphere, specific preparation method are：Target medicine is added in calcium phosphate bone cement liquid phase in step (3)
Thing；Or add drug target in the calcium phosphate bone cement slurry in step (4).
Compared with prior art, the present invention has advantages below and beneficial effect：
(1) microballoon of the invention not only has well-regulated spherical, and even size distribution；Microballoon in addition to rich in micropore,
A large amount of macropores are contained in its surface and inside, have good connectedness between internal void, such structure not only contributes to blood
Pipe is grown into freshman bone tissue；Secondly, microballoon has higher specific surface area, adds the contact between material and tissue fluid
Area, it may additionally facilitate the degradation speed of bone cement；Again, the calcium phosphate microsphere with loose structure can realize high drug load and bag
Envelope rate.
(2) negative pressure and ultrasonic cavitation that the present invention is formed using mixing center first, make locally to go out in liquid
Existing tension forms negative pressure, and under relatively low pressure, the gas being dissolved in liquid is escaped due to supersaturation from liquid, so as to
Many minute bubbles are formed in a liquid.
(3) present invention utilizes the shear action in high-speed agitating process, by controlling mixing speed to regulate and control the gas in slurry
Size is steeped, so as to control the quantity of calcium phosphate microsphere mesopore and size.
(4) porous calcium phosphate microsphere with surface macropore prepared by the present invention solves the surface of existing calcium phosphate microsphere
The shortcomings that lacking macropore, pore communication difference, prepared porous calcium phosphate microsphere surface and inside are dispersed with a large amount of micropores
And macropore, there is higher porosity and pore communication, and distribution of pores is more uniform.
(5) porous calcium phosphate microsphere with surface macropore prepared by the present invention is with multi-stage porous, its functional diversities, table
Face macropore can be that tissue and cell grow into offer adhesion and incision site to the inside of material, and internal macropore can be tissue and cell
Grown in material internal and space is provided, surface and internal capillary can be as the exchanges or transport of nutriment and products of cellular metabolism
Passage.
(6) the porous calcium phosphate microsphere preparation method of the present invention with surface macropore is simple, has more excellent
Biocompatible property, more preferable clinical application effect can be obtained, is had a extensive future.
Brief description of the drawings
Fig. 1 is the scanning electron microscopy of the porous calcium phosphate microsphere surface topography with surface macropore prepared by embodiment 1
Mirror photo.
Fig. 2 is the scanning electron microscopy of the porous calcium phosphate microsphere cross-section morphology with surface macropore prepared by embodiment 1
Mirror photo.
Embodiment
With reference to embodiment, the present invention is described in further detail, but the implementation of the present invention is not limited to this.
Embodiment 1
Be polysaccharide gum using gelatin, modified starch be thickener, " calcium dihydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system
There is the step of porous calcium phosphate microsphere of surface macropore to include for bone cement preparation：
(1) gelatin is dissolved in 30 DEG C of deionized waters with 6g/100mL ratio, the gelatin that concentration is 6% (w/v) is made
Solution；
(2) modified starch is dissolved in 25 DEG C of deionized waters with 2g/100mL ratio, it is 2% (w/v's) that concentration, which is made,
Modified starch solution；
(3) mixing of modified starch solution that the gelatin solution and step (2) obtained step (1) obtains, gelatin/change is obtained
Property starch mixed solution, the liquid phase as " calcium dihydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system bone cement；
(4) gelatin for obtaining step (3)/modified starch mixed solution and " calcium dihydrogen phosphate-type alpha tricalcium phosphate-carbonic acid
Calcium " system bone cement powder is sufficiently mixed by liquid-solid ratio 4mL/g, high-speed stirred, mixing speed 400r/min, and mixing time is
20min, " calcium dihydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system bone water slurry body rich in bubble is made；
(5) " calcium dihydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system bone water rich in bubble that will be obtained in step (4)
Slurry body is placed in ultrasonic oscillator, supersonic frequency 30kHz, ultrasonic time 5min；
(6) with the syringe that syringe needle internal diameter is 1.2mm by the " calcium dihydrogen phosphate-type alpha tricalcium phosphate-carbonic acid in step (5)
Calcium " system bone cement slurry is added drop-wise in liquid nitrogen, obtains freezing bone cement microballoon；Freezing bone cement microballoon is placed in 37 DEG C, phase
It is aquation to be conserved in 98% (percentage of water vapor in air) environment 2 days to humidity, vacuum drying, obtains with surface macropore
Porous calcium phosphate microsphere.
The pattern of microballoon is as shown in Figure 1：Microspherulite diameter is 2.2mm, and a large amount of macropores, and macropore size is distributed with microsphere surface
For 30~50 μm, microballoon internal structure pattern is as shown in Fig. 2 internal contain a large amount of holes, interconnected, internal holes between hole
Size is 120~160 μm, porosity 74.24%；External anti-disintegration experiment shows, by the porous calcium phosphate with surface macropore
Calcium microballoon is put into immersion in phosphate buffer solution (PBS) and observed after 15 days, and microballoon is not disintegrated.After external degradation 3 weeks,
The weight-loss ratio of porous calcium phosphate microsphere is 16.24%.
Embodiment 2
Be polysaccharide gum using converted starch, sodium alginate be thickener, " tetracalcium phosphate-bata-tricalcium phosphate-biphosphate
There is the preparation of calcium " system bone cement the step of porous calcium phosphate microsphere of surface macropore to include：
(1) converted starch is dissolved in 35 DEG C of deionized waters with 12g/100mL ratio, it is 12% (w/v) that concentration, which is made,
Converted starch solution；
(2) sodium alginate is dissolved in 30 DEG C of deionized waters with 2g/100mL ratio, it is 2% (w/v's) that concentration, which is made,
Sodium alginate soln；
(3) the sodium alginate soln mixing that the converted starch solution and step (2) obtained step (1) obtains, is become
Property starch/mixed solution of sodium alginate, the liquid phase as " tetracalcium phosphate-bata-tricalcium phosphate-calcium dihydrogen phosphate " system bone cement；
(4) converted starch/mixed solution of sodium alginate for obtaining step (3) and " tetracalcium phosphate-bata-tricalcium phosphate-phosphorus
Acid dihydride calcium " system bone cement powder is sufficiently mixed by liquid-solid ratio 5mL/g, high-speed stirred, mixing speed 600r/min, stirring
Time is 28min, and " tetracalcium phosphate-bata-tricalcium phosphate-calcium dihydrogen phosphate " system bone cement slurry rich in bubble is made；
(5) " tetracalcium phosphate-bata-tricalcium phosphate-calcium dihydrogen phosphate " system bone rich in bubble that will be obtained in step (4)
Cement slurry is placed in ultrasonic oscillator, supersonic frequency 16kHz, ultrasonic time 10min；
(6) with the syringe that syringe needle internal diameter is 1.5mm by the " tetracalcium phosphate-bata-tricalcium phosphate-di(2-ethylhexyl)phosphate in step (5)
Hydrogen calcium " system bone cement slurry is added drop-wise in liquid nitrogen, obtains freezing bone cement microballoon；Will freezing bone cement microballoon be placed in 25 DEG C,
Relative humidity is aquation to be conserved in 96% (percentage of water vapor in air) environment 3 days, vacuum drying, is obtained big with surface
The porous calcium phosphate microsphere in hole.
Microspherulite diameter is 2.6mm, and a large amount of macropores are distributed with microsphere surface, and macropore size is 40~70 μm, and inside is contained
A large amount of holes, it is interconnected between hole, inside bore dimension is 110~170 μm, porosity 76.16%；External anti-disintegration is real
To test and show, the porous calcium phosphate microsphere with surface macropore is put into immersion in phosphate buffer solution (PBS) observes after 18 days,
Microballoon is not disintegrated.After external degradation 3 weeks, the weight-loss ratio of porous calcium phosphate microsphere is 18.08%.
Embodiment 3
Be polysaccharide gum using xanthans, HPMC be thickener, " partially crystallized calcium phosphate-calcium monohydrogen phosphate " system
The step of system bone cement prepares the porous calcium phosphate microsphere with surface macropore includes：
(1) xanthans is dissolved in 40 DEG C of deionized waters with 8g/100mL ratio, the Huang that concentration is 8% (w/v) is made
Virgin rubber solution；
(2) HPMC is dissolved in 60 DEG C of deionized waters with 4g/100mL ratio, concentration is made as 4%
(w/v) HPMC solution；
(3) the HPMC solution mixing that the xanthan gum solution and step (2) obtained step (1) obtains, is obtained
To xanthans/HPMC mixed solution, the liquid as " partially crystallized calcium phosphate-calcium monohydrogen phosphate " system bone cement
Phase；
(4) xanthans for obtaining step (3)/HPMC mixed solution and " partially crystallized calcium phosphate-phosphoric acid
Hydrogen calcium " system bone cement powder is sufficiently mixed by liquid-solid ratio 2mL/g, high-speed stirred, mixing speed 1200r/min, during stirring
Between be 36min, be made rich in bubble " partially crystallized calcium phosphate-calcium monohydrogen phosphate " system bone cement slurry；
(5) " partially crystallized calcium phosphate-calcium monohydrogen phosphate " system bone cement slurry rich in bubble that will be obtained in step (4)
It is placed in ultrasonic oscillator, supersonic frequency 40kHz, ultrasonic time 12min；
(6) with the syringe that syringe needle internal diameter is 0.8mm by " partially crystallized calcium phosphate-calcium monohydrogen phosphate " system in step (5)
System bone cement slurry is added drop-wise in liquid nitrogen, obtains freezing bone cement microballoon；Freezing bone cement microballoon is placed in 35 DEG C, relative humidity
To conserve aquation in 100% (percentage of water vapor in air) environment 1 day, vacuum drying, obtain that there are the more of surface macropore
Hole calcium phosphate microsphere.
Microspherulite diameter is 2.1mm, and a large amount of macropores are distributed with microsphere surface, and macropore size is 30~60 μm, and inside is contained
A large amount of holes, it is interconnected between hole, inside bore dimension is 100~160 μm, porosity 68.16%；External anti-disintegration is real
To test and show, the porous calcium phosphate microsphere with surface macropore is put into immersion in phosphate buffer solution (PBS) observes after 21 days,
Microballoon is not disintegrated.After external degradation 3 weeks, the weight-loss ratio of porous calcium phosphate microsphere is 14.52%.
Embodiment 4
Be polysaccharide gum using dextrin, polyvinyl alcohol be thickener, " tetracalcium phosphate-type alpha tricalcium phosphate " system bone cement prepare
The step of porous calcium phosphate microsphere with surface macropore, includes：
(1) dextrin is dissolved in 25 DEG C of deionized waters with 20g/100mL ratio, the paste that concentration is 20% (w/v) is made
Smart solution；
(2) polyvinyl alcohol is dissolved in 45 DEG C of deionized waters with 0.1g/100mL ratio, it is 0.1% (w/ that concentration, which is made,
V) poly-vinyl alcohol solution；
(3) mixing of poly-vinyl alcohol solution that the dextrin solution and step (2) obtained step (1) obtains, dextrin/poly- is obtained
Ethene mixed alkoxide solution, the liquid phase as " tetracalcium phosphate-type alpha tricalcium phosphate " system bone cement；
(4) dextrin for obtaining step (3)/polyvinyl alcohol solution and " tetracalcium phosphate-type alpha tricalcium phosphate " system bone
Cement material is sufficiently mixed by liquid-solid ratio 3mL/g, high-speed stirred, mixing speed 1000r/min, mixing time 40min, is made
" tetracalcium phosphate-type alpha tricalcium phosphate " system bone cement slurry rich in bubble；
(5) " tetracalcium phosphate-type alpha tricalcium phosphate " the system bone cement slurry rich in bubble obtained in step (4) is placed in
In ultrasonic oscillator, supersonic frequency 28kHz, ultrasonic time 18min；
(6) with the syringe that syringe needle internal diameter is 0.5mm by " tetracalcium phosphate-type alpha tricalcium phosphate " system bone in step (5)
Cement slurry is added drop-wise in liquid nitrogen, obtains freezing bone cement microballoon；Will freezing bone cement microballoon be placed in 60 DEG C, relative humidity be
Aquation is conserved in 90% (percentage of water vapor in air) environment 4 days, vacuum drying, obtain the porous phosphorus with surface macropore
Sour calcium microballoon.
Microspherulite diameter is 1.8mm, and a large amount of macropores are distributed with microsphere surface, and macropore size is 20~60 μm, and inside is contained
A large amount of holes, it is interconnected between hole, inside bore dimension is 100~140 μm, porosity 67.46%；External anti-disintegration is real
To test and show, the porous calcium phosphate microsphere with surface macropore is put into immersion in phosphate buffer solution (PBS) observes after 17 days,
Microballoon is not disintegrated.After external degradation 3 weeks, the weight-loss ratio of porous calcium phosphate microsphere is 12.36%.
Embodiment 5
Be polysaccharide gum using soluble chitosan, pectin be thickener, " amorphous calcium phosphate-calcium monohydrogen phosphate " system bone water
It is clay to include for the step of porous calcium phosphate microsphere with surface macropore：
(1) soluble chitosan is dissolved in 80 DEG C of deionized waters with 16g/100mL ratio, concentration is made as 16%
(w/v) soluble chitosan solution；
(2) pectin is dissolved in 30 DEG C of deionized waters with 0.2g/100mL ratio, it is 0.2% (w/v's) that concentration, which is made,
Pectin solution；
(3) the pectin solution mixing that the soluble chitosan solution and step (2) obtained step (1) obtains, obtaining can
Soluble chitosan/pectin mixed solution, the liquid phase as " amorphous calcium phosphate-calcium monohydrogen phosphate " system bone cement；
(4) soluble chitosan for obtaining step (3)/pectin mixed solution and " amorphous calcium phosphate-calcium monohydrogen phosphate "
System bone cement powder is sufficiently mixed by liquid-solid ratio 4mL/g, high-speed stirred, mixing speed 1200r/min, and mixing time is
36min, " amorphous calcium phosphate-calcium monohydrogen phosphate " system bone cement slurry rich in bubble is made；
(5) " amorphous calcium phosphate-calcium monohydrogen phosphate " the system bone cement slurry rich in bubble obtained in step (4) is put
In ultrasonic oscillator, supersonic frequency 40kHz, ultrasonic time 30min；
(6) with the syringe that syringe needle internal diameter is 1.0mm by " amorphous calcium phosphate-calcium monohydrogen phosphate " system in step (5)
Bone cement slurry is added drop-wise in liquid nitrogen, obtains freezing bone cement microballoon；Will freezing bone cement microballoon be placed in 45 DEG C, relative humidity be
Aquation is conserved in 95% (percentage of water vapor in air) environment 5 days, vacuum drying, obtain the porous phosphorus with surface macropore
Sour calcium microballoon.
Microspherulite diameter is 2.3mm, and a large amount of macropores are distributed with microsphere surface, and macropore size is 40~80 μm, and inside is contained
A large amount of holes, it is interconnected between hole, inside bore dimension is 120~160 μm, porosity 72.52%；External anti-disintegration is real
To test and show, the porous calcium phosphate microsphere with surface macropore is put into immersion in phosphate buffer solution (PBS) observes after 20 days,
Microballoon is not disintegrated.After external degradation 3 weeks, the weight-loss ratio of porous calcium phosphate microsphere is 15.42%.
Embodiment 6
Be polysaccharide gum using guar gum, hydroxypropyl methyl cellulose be thickener, " tetracalcium phosphate-calcium monohydrogen phosphate " system
There is the step of porous calcium phosphate microsphere of surface macropore to include for bone cement preparation：
(1) guar gum is dissolved in 30 DEG C of deionized waters with 2g/100mL ratio, it is 2% (w/v's) that concentration, which is made,
Guar gum solution；
(2) hydroxypropyl methyl cellulose is dissolved in 80 DEG C of deionized waters with 5g/100mL ratio, concentration is made as 5%
(w/v) Gonak；
(3) Gonak that the guar gum solution and step (2) obtained step (1) obtains mixes
Close, guar gum/hydroxypropyl methyl cellulose mixed solution is obtained, as " tetracalcium phosphate-calcium monohydrogen phosphate " system bone cement
Liquid phase；
(4) guar gum for obtaining step (3)/hydroxypropyl methyl cellulose mixed solution and " tetracalcium phosphate-phosphoric acid hydrogen
Calcium " system bone cement powder is sufficiently mixed by liquid-solid ratio 5mL/g, high-speed stirred, mixing speed 600r/min, and mixing time is
20min, " tetracalcium phosphate-calcium monohydrogen phosphate " system bone cement slurry rich in bubble is made；
(5) " tetracalcium phosphate-calcium monohydrogen phosphate " the system bone cement slurry rich in bubble obtained in step (4) is placed in super
In acoustic wave oscillator, supersonic frequency 24kHz, ultrasonic time 16min；
(6) with the syringe that syringe needle internal diameter is 0.6mm by " tetracalcium phosphate-calcium monohydrogen phosphate " system bone water in step (5)
Slurry body is added drop-wise in liquid nitrogen, obtains freezing bone cement microballoon；Freezing bone cement microballoon is placed in 55 DEG C, relative humidity 99%
Aquation is conserved in (percentage of water vapor in air) environment 7 days, vacuum drying, obtain the porous calcium phosphate with surface macropore
Microballoon.
Microspherulite diameter is 2.2mm, and a large amount of macropores are distributed with microsphere surface, and macropore size is 35~80 μm, and inside is contained
A large amount of holes, it is interconnected between hole, inside bore dimension is 105~150 μm, porosity 71.18%；External anti-disintegration is real
To test and show, the porous calcium phosphate microsphere with surface macropore is put into immersion in phosphate buffer solution (PBS) observes after 18 days,
Microballoon is not disintegrated.After external degradation 3 weeks, the weight-loss ratio of porous calcium phosphate microsphere is 14.37%.
Embodiment 7
Be polysaccharide gum using Arabic gum, sodium carboxymethylcellulose be thickener, " calcium monohydrogen phosphate-type alpha tricalcium phosphate-carbonic acid
There is the preparation of calcium " system bone cement the step of porous calcium phosphate microsphere of surface macropore to include：
(1) Arabic gum is dissolved in 65 DEG C of deionized waters with 18g/100mL ratio, it is 18% (w/v) that concentration, which is made,
Gumwater；
(2) sodium carboxymethylcellulose is dissolved in 55 DEG C of deionized waters with 0.4g/100mL ratio, concentration, which is made, is
0.4% (w/v) carboxymethylcellulose sodium solution；
(3) the carboxymethylcellulose sodium solution mixing that the gumwater and step (2) obtained step (1) obtains,
Arabic gum/sodium carboxymethylcellulose mixed solution is obtained, as " calcium monohydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system bone water
The liquid phase of mud；
(4) Arabic gum for obtaining step (3)/sodium carboxymethylcellulose mixed solution and " calcium monohydrogen phosphate-alpha-phosphate three
Calcium-calcium carbonate " system bone cement powder is sufficiently mixed by liquid-solid ratio 4.5mL/g, high-speed stirred, mixing speed 1100r/min,
Mixing time is 35min, and " calcium monohydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system bone cement slurry rich in bubble is made；
(5) " calcium monohydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system bone cement rich in bubble that will be obtained in step (4)
Slurry is placed in ultrasonic oscillator, supersonic frequency 20kHz, ultrasonic time 24min；
(6) with the syringe that syringe needle internal diameter is 1.2mm by " calcium monohydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " in step (5)
System bone cement slurry is added drop-wise in liquid nitrogen, obtains freezing bone cement microballoon；Will freezing bone cement microballoon be placed in 35 DEG C, it is relatively wet
Spend to conserve aquation in 94% (percentage of water vapor in air) environment 6 days, vacuum drying, obtain that there are the more of surface macropore
Hole calcium phosphate microsphere.
(7) porous calcium phosphate microsphere obtained in step (6) is soaked into 30min, vacuum in 20 DEG C in GUNING ZHUSHEYE
Dry, obtain loading the porous calcium phosphate medicine microspheres of GUNING ZHUSHEYE.
(8) the porous calcium phosphate medicine microspheres of the load GUNING ZHUSHEYE obtained in step (7) are implanted to the stock of rabbit
At Cranial defect, layer-by-layer suture operative incision, the healing state of clinical follow operative incision.
Microspherulite diameter is 3.0mm, and a large amount of macropores are distributed with microsphere surface, and macropore size is 30~75 μm, and inside is contained
A large amount of holes, it is interconnected between hole, inside bore dimension is 100~140 μm, porosity 73.56%；External anti-disintegration is real
To test and show, the porous calcium phosphate microsphere with surface macropore is put into immersion in phosphate buffer solution (PBS) observes after 16 days,
Microballoon is not disintegrated.After external degradation 3 weeks, the weight-loss ratio of porous calcium phosphate microsphere is 13.24%.Porous calcium phosphate carries medicine
The envelop rate of medicine is 92% in microballoon；Postoperative 6 weeks histological findings show that newborn bone tissue can be grown into microballoon
Inside the formed gap of accumulation and porous microsphere, Bone Defect Repari works well.
Embodiment 8
Be polysaccharide gum using hydroxyethyl cellulose, oxidized starch be thickener, " calcium dihydrogen phosphate-type alpha tricalcium phosphate-carbonic acid
There is the preparation of calcium " system bone cement the step of porous calcium phosphate microsphere of surface macropore to include：
(1) hydroxyethyl cellulose is dissolved in 25 DEG C of deionized waters with 10g/100mL ratio, concentration is made as 10%
(w/v) hydroxyethyl cellulose solution；
(2) oxidized starch is dissolved in 60 DEG C of deionized waters with 3g/100mL ratio, it is 3% (w/v's) that concentration, which is made,
Oxidized starch solution；
(3) the oxidized starch solution mixing that the hydroxyethyl cellulose solution and step (2) obtained step (1) obtains, is obtained
To hydroxyethyl cellulose/oxidized starch mixed solution, as " calcium dihydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system bone cement
Liquid phase；
(4) hydroxyethyl cellulose for obtaining step (3)/oxidized starch mixed solution and " calcium dihydrogen phosphate-alpha-phosphate three
Calcium-calcium carbonate " system bone cement powder is sufficiently mixed by liquid-solid ratio 5mL/g, high-speed stirred, mixing speed 900r/min, is stirred
It is 25min to mix the time, and " calcium dihydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system bone cement slurry rich in bubble is made；
(5) " calcium dihydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system bone water rich in bubble that will be obtained in step (4)
Slurry body is placed in ultrasonic oscillator, supersonic frequency 18kHz, ultrasonic time 12min；
(6) with the syringe that syringe needle internal diameter is 1.0mm by the " calcium dihydrogen phosphate-type alpha tricalcium phosphate-carbonic acid in step (5)
Calcium " system bone cement slurry is added drop-wise in liquid nitrogen, obtains freezing bone cement microballoon；Freezing bone cement microballoon is placed in 37 DEG C, phase
It is aquation to be conserved in 96% (percentage of water vapor in air) environment 3 days to humidity, vacuum drying, obtains with surface macropore
Porous calcium phosphate microsphere.
(7) porous calcium phosphate microsphere obtained in step (6) is soaked into 30min, vacuum in 20 DEG C in injection bone peptide
Dry, obtain loading the porous calcium phosphate medicine microspheres of injection bone peptide.
(8) the porous calcium phosphate medicine microspheres of the load injection bone peptide obtained in step (7) are implanted to the stock of rabbit
At Cranial defect, layer-by-layer suture operative incision, the healing state of clinical follow operative incision.
Microspherulite diameter is 2.8mm, and a large amount of macropores are distributed with microsphere surface, and macropore size is 40~85 μm, and inside is contained
A large amount of holes, it is interconnected between hole, inside bore dimension is 110~150 μm, porosity 68.34%；External anti-disintegration is real
To test and show, the porous calcium phosphate microsphere with surface macropore is put into immersion in phosphate buffer solution (PBS) observes after 15 days,
Microballoon is not disintegrated.After external degradation 3 weeks, the weight-loss ratio of porous calcium phosphate microsphere is 11.26%.Porous calcium phosphate carries medicine
The envelop rate of medicine is 87% in microballoon；Postoperative 4 weeks histological findings show that newborn bone tissue can be grown into microballoon
Inside the formed gap of accumulation and porous microsphere, Bone Defect Repari works well.
Embodiment 9
Be polysaccharide gum using carragheen, polyvinyl alcohol be thickener, " partially crystallized calcium phosphate-calcium monohydrogen phosphate " system bone water
It is clay to include for the step of porous calcium phosphate microsphere with surface macropore：
(1) carragheen is dissolved in 40 DEG C of deionized waters with 15g/100mL ratio, it is 15% (w/v's) that concentration, which is made,
Carrageenan solutions；
(2) polyvinyl alcohol is dissolved in 60 DEG C of deionized waters with 2g/100mL ratio, it is 2% (w/v's) that concentration, which is made,
Poly-vinyl alcohol solution；
(3) the poly-vinyl alcohol solution mixing that the carrageenan solutions and step (2) obtained step (1) obtain, obtains OK a karaoke club
Glue/polyvinyl alcohol solution, the liquid phase as " partially crystallized calcium phosphate-calcium monohydrogen phosphate " system bone cement；
(4) vancomycin is added to carragheen/polyvinyl alcohol solution that step (3) obtains with 10mg/mL ratios
In, obtain vancomycin-carragheen/polyvinyl alcohol solution；
(5) by the vancomycin-carragheen/polyvinyl alcohol solution obtained in step (4) the and " part of step (4)
Crystallized calcium phosphate-calcium monohydrogen phosphate " system bone cement powder is sufficiently mixed by liquid-solid ratio 3.5mL/g, high-speed stirred, and mixing speed is
1100r/min, mixing time 36min, vancomycin-" partially crystallized calcium phosphate-calcium monohydrogen phosphate " system rich in bubble is made
System bone cement slurry；
(6) by the vancomycin rich in bubble obtained in step (5)-" partially crystallized calcium phosphate-calcium monohydrogen phosphate " system
Bone cement slurry is placed in ultrasonic oscillator, supersonic frequency 32kHz, ultrasonic time 26min；
(7) with the syringe that syringe needle internal diameter is 0.8mm by the vancomycin in step (5)-" partially crystallized calcium phosphate-phosphorus
Sour hydrogen calcium " system bone cement slurry is added drop-wise in liquid nitrogen, obtains freezing bone cement drug bearing microsphere；Bone cement drug bearing microsphere will be freezed
Be placed in 50 DEG C, relative humidity be that aquation 2 days is conserved in 90% (percentage of water vapor in air) environment, vacuum drying, obtain
Porous calcium phosphate drug bearing microsphere with surface macropore.
Drug bearing microsphere particle diameter is 1.8mm, and a large amount of macropores are distributed with microsphere surface, and macropore size is 25~85 μm, internal
Containing a large amount of holes, it is interconnected between hole, inside bore dimension is 100~140 μm, porosity 66.48%；It is anti-in vitro to collapse
Solution experiment shows, the porous calcium phosphate microsphere with surface macropore is put into after being soaked 16 days in phosphate buffer solution (PBS)
Observation, microballoon are not disintegrated.After external degradation 3 weeks, the weight-loss ratio of porous calcium phosphate drug bearing microsphere is 12.68%.It is porous
The envelop rate of calcium phosphate drug bearing microsphere is 96%.
Above-described embodiment is the preferable embodiment of the present invention, but embodiments of the present invention are not by the embodiment
Limitation, other any Spirit Essences without departing from the present invention with made under principle change, modification, replacement, combine, simplification,
Equivalent substitute mode is should be, is included within protection scope of the present invention.
Claims (9)
1. a kind of preparation method of the porous calcium phosphate microsphere material with surface macropore, it is characterised in that comprise the following steps：
(1) polysaccharide gum is dissolved in 25~80 DEG C of deionized waters, the polysaccharide gum solution that concentration is 2%~20%w/v is made；
(2) thickener is dissolved in 25~80 DEG C of deionized waters, the thickener soln that concentration is 0.1%~5%w/v is made；
(3) the thickener soln mixing that the polysaccharide gum solution and step (2) obtained step (1) obtains, obtains polysaccharide gum/thickening
Agent mixed solution, the liquid phase as calcium phosphate bone cement；
(4) polysaccharide gum for obtaining step (3)/thickener mixed solution and calcium phosphate bone cement powder are by 2~5mL/g of liquid-solid ratio
It is sufficiently mixed, stirred by 400~1200r/min of speed, mixing time is 20~40min, and the calcium phosphate rich in bubble is made
Bone cement slurry；
(5) the calcium phosphate bone cement slurry rich in bubble obtained in step (4) is placed in ultrasonic oscillator, supersonic frequency
For 16~40kHz, ultrasonic time is 5~30min；
(6) the calcium phosphate bone cement slurry in step (5) is added drop-wise to liquid nitrogen with the syringe that syringe needle internal diameter is 0.5~1.5mm
In, obtain freezing bone cement microballoon；The ring that bone cement microballoon is placed in 25~60 DEG C, relative humidity is 90%~100% will be freezed
Aquation is conserved in border 1~7 day, vacuum drying, obtain the porous calcium phosphate microsphere with surface macropore；The aperture of the macropore is
20~85 μm.
2. the preparation method of the porous calcium phosphate microsphere material according to claim 1 with surface macropore, its feature exist
In, polysaccharide gum described in step (1) is converted starch, gelatin, xanthans, soluble chitosan, hydroxyethyl cellulose, dextrin,
At least one of Arabic gum, carragheen, guar gum.
3. the preparation method of the porous calcium phosphate microsphere material according to claim 1 with surface macropore, its feature exist
In the thickener described in step (2) is modified starch, oxidized starch, sodium carboxymethylcellulose, HPMC, marine alga
At least one of sour sodium, polyvinyl alcohol, pectin, hydroxypropyl methyl cellulose.
4. the preparation method of the porous calcium phosphate microsphere material according to claim 1 with surface macropore, its feature exist
In the calcium phosphate bone cement described in step (4) is " tetracalcium phosphate-calcium monohydrogen phosphate " system bone cement, " calcium dihydrogen phosphate-α-phosphorus
Sour DFP-calcium carbonate " system bone cement, " tetracalcium phosphate-type alpha tricalcium phosphate " system bone cement, " tetracalcium phosphate-β-tricresyl phosphate
Calcium-calcium dihydrogen phosphate " system bone cement, " amorphous calcium phosphate-calcium monohydrogen phosphate " system bone cement, " partially crystallized calcium phosphate-phosphorus
Any one in sour hydrogen calcium " bone cement or " calcium monohydrogen phosphate-type alpha tricalcium phosphate-calcium carbonate " system bone cement.
5. prepared by the preparation method of the porous calcium phosphate microsphere material with surface macropore described in any one of Claims 1 to 4
The obtained porous calcium phosphate microsphere material with surface macropore, it is characterised in that the surface of the porous calcium phosphate microsphere and
Inside is dispersed with a large amount of micropores and macropore, is interconnected between hole, and internal macropore size is 100-160 μm.
6. the application of the porous calcium phosphate microsphere material with surface macropore described in claim 5, it is characterised in that the tool
There is the porous calcium phosphate microsphere material of surface macropore as drug carrier material.
7. the application of the porous calcium phosphate microsphere material according to claim 6 with surface macropore, it is characterised in that institute
It is drug bearing microsphere to state the porous calcium phosphate microsphere with surface macropore.
8. the application of the porous calcium phosphate microsphere material according to claim 7 with surface macropore, it is characterised in that institute
Drug bearing microsphere is stated, specific preparation method is：The microballoon made is soaked in drug solution, is loaded into by the form of liquid phase adsorption
Medicine.
9. the application of the porous calcium phosphate microsphere material according to claim 7 with surface macropore, it is characterised in that institute
Drug bearing microsphere is stated, specific preparation method is：Target is added in calcium phosphate bone cement liquid phase the claim 1 the step of in (3)
Medicine；Or add drug target in the calcium phosphate bone cement powder the claim 1 the step of in (4).
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| CN110090321B (en) * | 2018-01-29 | 2022-05-13 | 上海瑞邦生物材料有限公司 | Porous calcium phosphate particle and preparation method thereof |
| CN108144113A (en) * | 2018-02-12 | 2018-06-12 | 华南理工大学 | A kind of porous bone repair material of bioactivity glass and preparation method thereof |
| CN109020701A (en) * | 2018-09-11 | 2018-12-18 | 浙江世佳科技有限公司 | A kind of high-performance bio bacterial manure |
| CN109106986B (en) * | 2018-09-14 | 2020-12-25 | 广州润虹医药科技股份有限公司 | Medicine controlled-release calcium phosphate bone cement composite microsphere, preparation method and application thereof |
| CN109260511A (en) * | 2018-09-14 | 2019-01-25 | 广州润虹医药科技股份有限公司 | A kind of Injectable porous calcium phosphate bone cement and preparation method thereof |
| CN109260523A (en) * | 2018-09-14 | 2019-01-25 | 广州润虹医药科技股份有限公司 | A kind of calcium phosphate bone cement complex microsphere and its preparation method and application |
| CN113135769B (en) * | 2021-04-09 | 2022-07-26 | 华南理工大学 | Surface-coated modified porous calcium phosphate ceramic microsphere and preparation method and application thereof |
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